Novel amines as pharmaceutical agents

ABSTRACT

Novel amines of formulas 1A and 1B  
                 
 
     are disclosed and are useful as agents in the treatment of epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, inflammatory diseases, and gastrointestinal disorders, especially IBS. Processes for the preparation and intermediates useful in the preparation are also disclosed.

BACKGROUND OF THE INVENTION

[0001] Compounds of formula

[0002] wherein R₁ is hydrogen or a lower alkyl radical and n is 4, 5, or6 are known in U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No.4,087,544. The uses disclosed are: protective effect against crampinduced by thiosemicarbazide; protective action against cardiazolecramp; the cerebral diseases, epilepsy, faintness attacks, hypokinesia,and cranial traumas; and improvement in cerebral functions. Thecompounds are useful in geriatric patients. The patents are herebyincorporated by reference.

[0003] Compounds of formula

[0004] wherein R₁ is a straight or branched alkyl group having from 1 to6 carbon atoms, phenyl, or cycloalkyl having from 3 to 6 carbon atoms;R₂ is hydrogen or methyl; and R₃ is hydrogen, methyl, or carboxyl areknown in U.S. Pat. No. 5,563,175 and various divisionals. These patentsare hereby incorporated by reference.

SUMMARY OF THE INVENTION

[0005] The compounds of the instant invention are novel amines and theirpharmaceutically acceptable salts useful in a variety of disorders. Thedisorders include: epilepsy, faintness attacks, hypokinesia, cranialdisorders, neurodegenerative disorders, depression, anxiety, panic,pain, neuropathological disorders, inflammation, and gastrointestinaldisorders.

[0006] The compounds of the invention are those of formulas 1A and 1Bbelow.

[0007] Preferred compounds are those of formulas 1A and 1B wherein R isa sulfonamide selected from —NHSO₂R¹⁵ or —SO₂NHR¹⁵ wherein R¹⁵ isstraight or branched alkyl or trifluoromethyl.

[0008] Especially preferred are:

[0009] 4-Methyl-2-(1H-tetrazol-5-ylmethyl)-pentylamine;

[0010] 3-(2-Aminomethyl-4-methyl-pentyl)-4H-[1,2,4]oxadiazole-5-thione,HCl;

[0011] 3-(2-Aminomethyl-4-methyl-pentyl)-4H-[1,2,4]oxadiazole-5-one,HCl;

[0012] (2-Aminomethyl-4-methyl-pentyl)-phosphonic acid;

[0013] 3-(3-Amino-2-cyclopentyl-propyl)-4H-[1,2,4]oxadiazol-5-one;

[0014] 3-(3-Amino-2-cyclopentyl-propyl)-4H-[1,2,4]thiadiazol-5-one;

[0015]2-Cyclopentyl-3-(2-oxo-2,3-dihydro-2λ⁴-[1,2,3,5]oxathiadiazol-4-yl)-propylamine;

[0016] 3-(3-Amino-2-cyclobutyl-propyl)-4H-[1,2,4]oxadiazol-5-one;

[0017] 3-(3-Amino-2-cyclobutyl-propyl)-4H-[1,2,4]thiadiazol-5-one; and

[0018]2-Cyclobutyl-3-(2-oxo-2,3-dihydro-2λ⁴-[1,2,3,5]oxathiadiazol-4-yl)-propylamine.

[0019] Other preferred compounds are those of formulas 1A and 1B whereinR is a phosphonic acid, —PO₃H₂.

[0020] Other preferred compounds are those of Formulas 1A and 1B wherein

[0021] Especially preferred are:

DETAILED DESCRIPTION OF THE INVENTION

[0022] The amines of the instant invention are compounds of formula 1Aand 1B and the pharmaceutically acceptable salts thereof.

[0023] The compounds of the invention are those of formula

[0024] or a pharmaceutically acceptable salt thereof wherein:

[0025] n is an integer of from 0 to 2;

[0026] R is sulfonamide,

[0027] amide,

[0028] phosphonic acid,

[0029] heterocycle,

[0030] sulfonic acid, or

[0031] hydroxamic acid;

[0032] A is hydrogen or methyl; and

[0033] B is

[0034] straight or branched alkyl of from 1 to 11 carbons, or

[0035] —(CH₂)₁₋₄—Y—(CH₂)₀₋₄-phenyl wherein Y is —O—, —S—, —NR′₃ wherein

[0036] R′₃ is alkyl of from 1 to 6 carbons, cycloalkyl of from 3 to 8carbons, benzyl or phenyl wherein benzyl or phenyl can be unsubstitutedor substituted with from 1 to 3 substituents each independently selectedfrom alkyl, alkoxy, halogen, hydroxy, carboxy, carboalkoxy,trifluoromethyl, and nitro.

[0037] Since amino acids are amphoteric, pharmacologically compatiblesalts can be salts of appropriate inorganic or organic acids, forexample, hydrochloric, sulphuric, phosphoric, acetic, oxalic, lactic,citric, malic, salicylic, malonic, maleic, succinic, methanesulfonicacid, and ascorbic. Starting from corresponding hydroxides orcarbonates, salts with alkali metals or alkaline earth metals, forexample, sodium, potassium, magnesium, or calcium are formed. Salts withquaternary ammonium ions can also be prepared with, for example, thetetramethyl-ammonium ion. The carboxyl group of the amino acids can beesterified by known means.

[0038] Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

[0039] The terms used to define the invention are as described below.

[0040] Sulfonamides are those of formula —NHSO₂R¹⁵ or —SO₂NHR¹⁵ whereinR¹⁵ is a straight or branched alkyl group of from 1 to 6 carbons or atrifluoromethyl.

[0041] Amides are compounds of formula —NHCOR¹² wherein R¹² is straightor branched alkyl of from 1 to 6 carbons, benzyl, and phenyl.

[0042] Phosphonic acids are —PO₃H₂.

[0043] Sulfonic acids are —SO₃H.

[0044] Hydroxamic acid is

[0045] Heterocycles are groups of from 1 to 2 rings, with from 1 to 6heteroatoms selected from oxygen, nitrogen, and sulfur.

[0046] Preferred heterocycles are

[0047] The term alkyl is a straight or branched group of from 1 to 11carbon atoms including but not limited to methyl, ethyl, propyl,n-propyl, isopropyl, butyl, 2-butyl, tert-butyl, pentyl, hexyl, andn-hexyl, heptyl, octyl, nonyl, decyl, and undecyl except as whereotherwise stated.

[0048] The cycloalkyl groups are from 3 to 8 carbons and arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl unless otherwise stated.

[0049] The benzyl and phenyl groups may be unsubstituted or substitutedby from 1 to 3 substituents selected from hydroxy, carboxy, carboalkoxy,halogen, CF₃, nitro, alkyl, and alkoxy. Preferred are halogens.

[0050] Alkoxy is as defined above for alkyl.

[0051] Halogen is fluorine, chlorine, and bromine and preferred arefluorine and chlorine.

[0052] Carboalkoxy is —COOalkyl wherein alkyl is as described above.Preferred are carbomethoxy and carboethoxy.

[0053] Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

[0054] Certain of the compounds of the present invention possess one ormore chiral centers and each center may exist in the R(D) or S(L)configuration. The present invention includes all enantiomeric andepimeric forms as well as the appropriate mixtures thereof.

[0055] The radioligand binding assay using [³H]gabapentin and the α₂δsubunit derived from porcine brain tissue was used (“The NovelAnti-convulsant Drug, Gabapentin, Binds to the α₂δ Subunit of a CalciumChannel”, Gee N. S., et al., J. Biol Chem, 1996;271(10):5768-5776).

[0056] The compounds of the invention show good binding affinity to theα₂δ subunit. Gabapentin (Neurontin®) is about 0.10 to 0.12 μM in thisassay. Since the compounds of the instant invention also bind to thesubunit, they are expected to exhibit pharmacologic propertiescomparable to gabapentin. For example, as agents for convulsions,anxiety, and pain. TABLE 1

Vogel α2δ Pain Model Conflict DBA2 Assay % MPE % of % Protection R IC₅₀(μM) 1 Hr 2 Hr CI-1008 1 Hr 2 Hr

2.47 0 0 0.0 0 0

>10 0 0

1.52 PO₃H₂ >10 0 0

[0057] The compounds of the invention are related to Neurontin®, amarketed drug effective in the treatment of epilepsy. Neurontin® is1-(aminomethyl)-cyclohexaneacetic acid of structural formula

[0058] Preferred novel gabapentin and isobutyl-GABA analogs, theirderivatives, and pharmaceutically acceptable salts are useful in thetreatment of a variety of disorders including epilepsy, faintnessattacks, hypokinesia, cranial disorders, neurodegenerative disorders,depression, anxiety, panic, pain, and neuropathological disorders. Thecompounds are of the general formula:

[0059] a pharmaceutically acceptable salt thereof or a prodrug thereof,where n=0,1,2, m=0,1,2,3, and R can be sulfonamides of the generalformula —NHSO₂R¹ or —SO₂NHR¹ where R¹ is H or C₁-C₄ straight or branchedchain alkyl or trifluoromethyl. R may also be an amide of the generalformula —NHCOR¹. Or R may also be a phosphonic acid —PO₃H₂ (Lipinski C.A., Ann. Rep. Med. Chem., 21:283 (1986)).

[0060] The compounds of the invention are also expected to be useful inthe treatment of epilepsy.

[0061] The present invention also relates to therapeutic use of thecompounds of the mimetic as agents for neurodegenerative disorders.

[0062] Such neurodegenerative disorders are, for example, Alzheimer'sdisease, Huntington's disease, Parkinson's disease, Amyotrophic LateralSclerosis, and epilepsy.

[0063] The present invention also covers treating neurodegenerativedisorders termed acute brain injury. These include but are not limitedto: stroke, head trauma, and asphyxia.

[0064] Stroke refers to a cerebral vascular disease and may also bereferred to as a cerebral vascular incident (CVA) and includes acutethromboembolic stroke. Stroke includes both focal and global ischemia.Also, included are transient cerebral ischemic attacks and othercerebral vascular problems accompanied by cerebral ischemia such as in apatient undergoing carotid endarterectomy specifically or othercerebrovascular or vascular surgical procedures in general, ordiagnostic vascular procedures including cerebral angiography and thelike.

[0065] Pain refers to acute as well as chronic pain.

[0066] Acute pain is usually short-lived and is associated withhyperactivity of the sympathetic nervous system. Examples arepostoperative pain and allodynia.

[0067] Chronic pain is usually defined as pain persisting from 3 to 6months and includes somatogenic pains and psychogenic pains. Other painis nociceptive.

[0068] Still other pain is caused by injury or infection of peripheralsensory nerves. It includes, but is not limited to pain from peripheralnerve trauma, herpes virus infection, diabetes mellitus, causalgia,plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathicpain is also caused by nerve damage from chronic alcoholism, humanimmunodeficiency virus infection, hypothyroidism, uremia, or vitamindeficiencies. Neuropathic pain includes, but is not limited to paincaused by nerve injury such as, for example, the pain diabetics sufferfrom.

[0069] Psychogenic pain is that which occurs without an organic originsuch as low back pain, atypical facial pain, and chronic headache.

[0070] Other types of pain are: inflammatory pain, osteoarthritic pain,trigeminal neuralgia, cancer pain, diabetic neuropathy, restless legsyndrome, acute herpetic and postherpetic neuralgia, causalgia, brachialplexus avulsion, occipital neuralgia, gout, phantom limb, bum, and otherforms of neuralgia, neuropathic and idiopathic pain syndrome.

[0071] Other incidents are head trauma, spinal cord trauma, or injuryfrom general anoxia, hypoxia, hypoglycemia, and hypotension as well assimilar injuries seen during procedures from embole, hyperfusion, andhypoxia.

[0072] The instant invention would be useful in a range of incidents,for example, during cardiac bypass surgery, in incidents of intracranialhemorrhage, in perinatal asphyxia, in cardiac arrest, and statusepilepticus.

[0073] A skilled physician will be able to determine the appropriatesituation in which subjects are susceptible to or at risk of, forexample, stroke as well as suffering from stroke for administration bymethods of the present invention.

[0074] The compounds of the invention are also expected to be useful inthe treatment of depression. Depression can be the result of organicdisease, secondary to stress associated with personal loss, oridiopathic in origin. There is a strong tendency for familial occurrenceof some forms of depression suggesting a mechanistic cause for at leastsome forms of depression. The diagnosis of depression is made primarilyby quantification of alterations in patients' mood. These evaluations ofmood are generally performed by a physician or quantified by aneuropsychologist using validated rating scales, such as the HamiltonDepression Rating Scale or the Brief Psychiatric Rating Scale. Numerousother scales have been developed to quantify and measure the degree ofmood alterations in patients with depression, such as insomnia,difficulty with concentration, lack of energy, feelings ofworthlessness, and guilt. The standards for diagnosis of depression aswell as all psychiatric diagnoses are collected in the Diagnostic andStatistical Manual of Mental Disorders (Fourth Edition) referred to asthe DSM-IV-R manual published by the American Psychiatric Association,1994.

[0075] GABA is an inhibitory neurotransmitter with the central nervoussystem. Within the general context of inhibition, it seems likely thatGABA-mimetics might decrease or inhibit cerebral function and mighttherefore slow function and decrease mood leading to depression.

[0076] The compounds of the instant invention may produce ananticonvulsant effect through the increase of newly created GABA at thesynaptic junction. If gabapentin does indeed increase GABA levels or theeffectiveness of GABA at the synaptic junction, then it could beclassified as a GABA-mimetic and might decrease or inhibit cerebralfunction and might, therefore, slow function and decrease mood leadingto depression.

[0077] The compounds of the invention will be useful in the treatment ofgastrointestinal disorders, especially irritable bowel syndrome.

[0078] The fact that a GABA agonist or GABA-mimetic might work just theopposite way by increasing mood and thus, be an antidepressant, is a newconcept, different from the prevailing opinion of GABA activityheretofore.

[0079] The compounds of the instant invention are also expected to beuseful in the treatment of anxiety and of panic as demonstrated by meansof standard pharmacological procedures.

Matereal and Methods

[0080] Carrageenin-Induced Hyperalgesia

[0081] Nociceptive pressure thresholds were measured in the rat pawpressure test using an analgesymeter (Randall-Sellitto Method: RandallL. O., Sellitto J. J., A method for measurement of analgesic activity oninflamed tissue. Arch. Int. Pharmacodyn., 4:409-419 (1957)). MaleSprague-Dawley rats (70-90 g) were trained on this apparatus before thetest day. Pressure was gradually applied to the hind paw of each rat andnociceptive thresholds were determined as the pressure (g) required toelicit paw withdrawal. A cutoff point of 250 g was used to prevent anytissue damage to the paw. On the test day, two to three baselinemeasurements were taken before animals were administered 100 μL of 2%carrageenin by intraplantar injection into the right hind paw.Nociceptive thresholds were taken again 3 hours after carrageenin toestablish that animals were exhibiting hyperalgesia. Animals were dosedwith either gabapentin (3-300 mg/kg, s.c.), morphine (3 mg/kg, s.c.), orsaline at 3.5 hours after carrageenin and nociceptive thresholds wereexamined at 4, 4.5, and 5 hours post carrageenin.

[0082] Semicarbazide-Induced Tonic Seizures

[0083] Tonic seizures in mice are induced by subcutaneous administrationof semicarbazide (750 mg/kg). The latency to the tonic extension offorepaws is noted. Any mice not convulsing within 2.0 hours aftersemicarbazide are considered protected and given a maximum latency scoreof 120 minutes.

[0084] Animals

[0085] Male Hooded Lister rats (200-250 g) are obtained from Interfauna(Huntingdon, UK) and male TO mice (20-25 g) are obtained from Bantin andKingman (Hull, UK). Both rodent species are housed in groups of six. TenCommon Marmosets (Callithrix Jacchus) weighing between 280 and 360 g,bred at Manchester University Medical School (Manchester, UK) are housedin pairs. All animals are housed under a 12-hour light/dark cycle(lights on at 07.00 hour) and with food and water ad libitum.

[0086] Drug Administration

[0087] Drugs are administered either intraperitoneally (IP) orsubcutaneously (SC) 40 minutes before the test in a volume of 1 mL/kgfor rats and marmosets and 10 mL/kg for mice.

[0088] Mouse Light/Dark Box

[0089] The apparatus is an open-topped box, 45 cm long, 27 cm wide, and27 cm high, divided into a small (⅖) and a large (⅗) area by a partitionthat extended 20 cm above the walls (Costall B., et al., Exploration ofmice in a black and white box: validation as a model of anxiety.Pharmacol. Biochem. Behav., 32:777-785 (1989)).

[0090] There is a 7.5×7.5 cm opening in the center of the partition atfloor level. The small compartment is painted black and the largecompartment white. The white compartment is illuminated by a 60-Wtungsten bulb. The laboratory is illuminated by red light. Each mouse istested by placing it in the center of the white area and allowing it toexplore the novel environment for 5 minutes. The time spent in theilluminated side is measured (Kilfoil T., et al., Effects of anxiolyticand anxiogenic drugs on exploratory activity in a simple model ofanxiety in mice. Neuropharmacol., 28:901-905 (1989)).

[0091] Rat Elevated X-Maze

[0092] A standard elevated X-maze (Handley S. L., et al., Effects ofalpha-adrenoceptor agonists and antagonists in a maze-exploration modelof ‘fear’-motivated behavior. Naunyn-Schiedeberg's Arch. Pharmacol.,327:1-5 (1984)), was automated as previously described (Field, et al.,Automation of the rat elevated X-maze test of anxiety. Br. J.Pharmacol., 102(Suppl):304P (1991)). The animals are placed on thecenter of the X-maze facing one of the open arms. For determininganxiolytic effects the entries and time spent on the end half sectionsof the open arms is measured during the 5-minute test period (Costall,et al., Use of the elevated plus maze to assess anxiolytic potential inthe rat. Br. J. Pharmacol., 96(Suppl):312P (1989)).

[0093] Marmoset Human Threat Test

[0094] The total number of body postures exhibited by the animal towardsthe threat stimulus (a human standing approximately 0.5 m away from themarmoset cage and staring into the eyes of the marmoset) is recordedduring the 2-minute test period. The body postures scored are slitstares, tail postures, scent marking of the cage/perches, piloerection,retreats, and arching of the back. Each animal is exposed to the threatstimulus twice on the test day before and after drug treatment. Thedifference between the two scores is analyzed using one-way analysis ofvariance followed by Dunnett's t-test. All drug treatments are carriedout SC at least 2 hours after the first (control) threat. Thepretreatment time for each compound is 40 minutes.

[0095] Rat Conflict Test

[0096] Rats are trained to press levers for food reward in operantchambers. The schedule consists of alternations of four 4-minuteunpunished periods on variable interval of 30 seconds signaled bychamber lights on and three 3-minute punished periods on fixed ratio 5(by footshock concomitant to food delivery) signaled by chamber lightsoff. The degree of footshock is adjusted for each rat to obtainapproximately 80% to 90% suppression of responding in comparison withunpunished responding. Rats receive saline vehicle on training days.

[0097] The compounds of the instant invention are also expected to beuseful in the treatment of pain and phobic disorders (Am. J. PainManag., 5:7-9 (1995)).

[0098] The compounds of the instant invention are also expected to beuseful in treating the symptoms of manic, acute or chronic, singleupside, or recurring depression. They are also expected to be useful intreating and/or preventing bipolar disorder (U.S. Pat. No. 5,510,381).

[0099] TNBS-Induced Chronic Visceral Allodynia in Rats

[0100] Injections of trinitrobenzene sulfonic (TNBS) into the colon havebeen found to induce chronic colitis. In human, digestive disorders areoften associated with visceral pain. In these pathologies, the visceralpain threshold is decreased indicating a visceral hypersensitivity.Consequently, this study was designed to evaluate the effect ofinjection of TNBS into the colon on visceral pain threshold in aexperimental model of colonic distension.

[0101] Animals and Surgery

[0102] Male Sprague-Dawley rats (Janvier, Le Genest-St-Ilse, France)weighing 340-400 g are used. The animals are housed 3 per cage in aregulated environment (20±1° C., 50±5% humidity, with light 8:00 am to8:00 pm). Under anesthesia (ketamine 80 mg/kg ip; acepromazin 12 mg/kgip), the injection of TNBS (50 mg/kg) or saline (1.5 mL/kg) is performedinto the proximal colon (1 cm from the cecum). After the surgery,animals are individually housed in polypropylene cages and kept in aregulated environment (20±1° C., 50±5% humidity, with light 8:00 am to8:00 pm) during 7 days.

[0103] Experimental Procedure

[0104] At Day 7 after TNBS administration, a balloon (5-6 cm length) isinserted by anus and kept in position (tip of balloon 5 cm from theanus) by taping the catheter to the base of the tail. The balloon isprogressively inflated by step of 5 mm Hg, from 0 to 75 mm Hg, each stepof inflation lasting 30 seconds. Each cycle of colonic distension iscontrolled by a standard barostat (ABS, St-Dié, France). The thresholdcorresponds to the pressure which produced the first abdominalcontraction and the cycle of distension is then discontinued. Thecolonic threshold (pressure expressed in mm Hg) is determined afterperformance of four cycles of distension on the same animal.

[0105] Determination of the Activity of the Compound

[0106] Data is analyzed by comparing test compound-treated group withTNBS-treated group and control group. Mean and sem are calculated foreach group. The antiallodynic activity of the compound is calculated asfollows:

Activity (%)=(group C−group T)/(group A−group T)

[0107] Group C: mean of the colonic threshold in the control group

[0108] Group T: mean of the colonic threshold in the TNBS-treated group

[0109] Group A: mean of the colonic threshold in the testcompound-treated group

[0110] Statistical Analysis

[0111] Statistical significance between each group was determined byusing a one-way ANOVA followed by Student's unpaired t-test. Differenceswere considered statistically significant at p<0.05.

[0112] Compounds

[0113] TNBS is dissolved in EtOH 30% and injected under a volume of 0.5mL/rat. TNBS is purchased from Fluka.

[0114] Oral administration of the test compound or its vehicle isperformed 1 hour before the colonic distension cycle.

[0115] Sub-cutaneous administration of the test compound or its vehicleis performed 30 minutes before the colonic distension cycle.

[0116] The compounds of the present invention can be prepared andadministered in a wide variety of oral and parenteral dosage forms.Thus, the compounds of the present invention can be administered byinjection, that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either a compound of Formula I or a correspondingpharmaceutically acceptable salt of a compound of Formula I.

[0117] For preparing pharmaceutical compositions from the compounds ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

[0118] In powders, the carrier is a finely divided solid which is in amixture with the finely divided active component.

[0119] In tablets, the active component is mixed with the carrier havingthe necessary binding properties in suitable proportions and compactedin the shape and size desired.

[0120] The powders and tablets preferably contain from five or ten toabout seventy percent of the active compound. Suitable carriers aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

[0121] For preparing suppositories, a low melting wax, such as a mixtureof fatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

[0122] Liquid form preparations include solutions, suspensions, andemulsions, for example, water or water propylene glycol solutions. Forparenteral injection liquid preparations can be formulated in solutionin aqueous polyethylene glycol solution.

[0123] Aqueous solutions suitable for oral use can be prepared bydissolving the active component in water and adding suitable colorants,flavors, stabilizing and thickening agents as desired.

[0124] Aqueous suspensions suitable for oral use can be made bydispersing the finely divided active component in water with viscousmaterial, such as natural or synthetic gums, resins, methylcellulose,sodium carboxymethylcellulose, and other well-known suspending agents.

[0125] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

[0126] The pharmaceutical preparation is preferably in unit dosage form.In such form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

[0127] The quantity of active component in a unit dose preparation maybe varied or adjusted from 0.1 mg to 1 g according to the particularapplication and the potency of the active component. In medical use thedrug may be administered three times daily as, for example, capsules of100 or 300 mg. The composition can, if desired, also contain othercompatible therapeutic agents.

[0128] In therapeutic use, the compounds utilized in the pharmaceuticalmethod of this invention are administered at the initial dosage of about0.01 mg to about 100 mg/kg daily. A daily dose range of about 0.01 mg toabout 100 mg/kg is preferred. The dosages, however, may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe art. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

[0129] R may also be a heterocycle such as tetrazole

[0130] or other heterocycles which have been used as replacements forCO₂H, such as

[0131] (Kohara Y., Kubo K., Imamiya E., Wada T., Inada Y., and Naka T.,J. Med. Chem., 39:5228 (1996)).

[0132] Sulfonic and hydroxamic acids are also preferred. Tetrazoles ofFormula 1A can be synthesized by the route outlined in Scheme 1.

[0133] The following examples are illustrative of the instant invention;they are not intended to limit the scope.

EXAMPLE 1

[0134]4-Methyl-2-(1H-tetrazol-5-ylmethyl)-pentylamine

[0135] Compound 3 in Scheme 1{2-[(2-Cyano-ethylcarbamoyl)-methyl]-4-methyl-pentyl}-carbamic acidtert-butyl ester

[0136] A solution of compound 2 (8.0 g, 0.03 mol) (prepared in the usualmanner from (BOC)₂ and pregabalin) was taken up in 250 mL dry THF andcooled in an ice water bath. Triethyl amine (4.62 mL, 0.033 mol) wasadded followed by the addition of isobutyle chloroformate (4 mL, 0.031mol). The reaction was stirred at 0° C. for about 15 minutes duringwhich time a precipitate formed. In a separate flask was placed3-aminoproprionitrile fumarate (3.95 g, 0.03 mol) in 35 mL of 1 M NaOHand 300 mL of THF. This mixture was cooled to 0° C. and treated with themixed anhydride formed above in four portions. Before each portion wasadded, 35 mL of 1 M NaOH was added to the mixture. The reaction wasstirred for 24 hours and was then concentrated to remove THF. Theresulting aqueous was extracted with three times ethyl acetate. Thecombined organic extracts were washed with brine, dried over magnesiumsulfate. The solvents were removed under reduced pressure to give 6.6 ggreen oil. MS(APCI) m/z 312 (M+1).

[0137] Compound 4 in Scheme 1[4-Methyl-2-(1-(2-cyano-ethyl)-tetrazol-5-ylmethyl)-pentyl]-carbamicacid tert-butyl ester and Compound 5[4-Methyl-2-(1H-tetrazol-5-ylmethyl)-pentyl]-carbamic acid tert-butylester.

[0138] The cyanoamide (6.5 g, 0.0209 mol) and triphenylphosphine (11.06g, 0.042 mol) were dissolved in 300 mL of dry THF. The solution wastreated with DEAD (6.7 mL, 0.0425 mol) and TMSN₃ (5.75 mL, 0.043 mol).The reaction was stirred for 24 hours, and the reaction mixture wascooled to 0° C. and treated with 900 mL of an aqueous solutioncontaining 46.9 g of (NH₄)₂Ce(IV)NO₃. The reaction mixture wasconcentrated to remove THF and extracted with three portions of CH₂Cl₂.The combined organic layers were dried with brine and Na₂SO₄ and thesolvents were removed under reduced pressure to give a clear oil whichwas passed through a plug of silicagel to give the product admixed withtriphenylphospine oxide. This crude mixture was dissolved in 200 mL THFand 50 mL of 2N NaOH. The mixture was heated to reflux for 2 hours thenstirred at room temperature overnight. The THF was removed under reducedpressure and the resulting residue diluted with water. After extractionwith ether, the aqueous phase was acidified to pH 7 and extracted with21 mL of 4N HCl. The aqueous phase was then saturated with solid KH₂PO₄.The aqueous mixture was extracted with CH₂Cl₂. The organic extracts werewashed with brine and dried over Na₂SO₄. Evaporation of the organicsolvents under reduced pressure resulted in isolation of 3.4 g of anamber oil.

[0139] 4-Methyl-2-(1H-tetrazol-5-ylmethyl)-pentylamine

[0140] The material from the previous step (0.9 g, 3.18 mmol) was takenup in 20 mL of 4 M HCl in dioxane. The reaction was allowed to stand for1 hour. A solid formed, 10 mL of ether was added, and the reaction wasfiltered to give 780 mg white solid. MS(APCI) m/z 184 (M+1).

EXAMPLE 2

[0141] IsobutylGABA oxadiazolonethione (G) Is Also Named3-(2-Aminomethyl-4-methyl-pentyl)-4H-[1,2,4]oxadiazole-5-thione; HCl

[0142] BOC-IsobutylGABA (B)

[0143] A solution of di-tert-butyl dicarbonate (13.1 g, 0.06 mol) in THF(200 mL) was added, over a 10-minute period, to a solution ofisobutylGABA (9.95 g, 0.056 mol) in 1N NaOH (125 mL) and THF (50 mL)cooled in an ice-water bath. The reaction mixture was stirred at roomtemperature 3 hours, concentrated to remove THF, saturated withsaturated KH₂PO₄ and extracted 3× EtOAc. The extracts were washed 2×brine, dried over MgSO₄, and evaporated to yield 13.8 g (95%) of a whitesolid, mp 84-88° C. MS (APCI) m/z 260 (M+1).

[0144] BOC-IsobutylGABA amide (C)

[0145] A solution of BOC-IsobutylGABA (6.78 g, 0.026 mol) andtriethylamine (3.0 g, 0.030 mol) was cooled to 0° C. and isobutylchloroformate (3.9 g, 0.029 mol) was slowly added. After stirring 20minutes at 0° C., ammonia gas was bubbled into the reaction mixture for30 minutes, and then the mixture was stirred at room temperature 18hours. The mixture was concentrated to remove THF, suspended in water,and extracted 3× EtOAc. The extracts were washed 1×10% Na₂CO₃, 2× brine,and dried over Na₂SO₄. Evaporation yielded 4.9 g (73%) of an oil whichwas used without further purification. MS (APCI) m/z 259 (M+1).

[0146] BOC-IsobutylGABA nitrile (D)

[0147] A solution of BOC-IsobutylGABA amide (4.6 g, 0.0178 mol) in DMF(15 mL) was added, all at once, to cyanuric chloride (1.66 g, 0.009 mol)and stirred 30 minutes at room temperature. The reaction mixture waspoured into a cold solution of NaHCO₃ (4.2 g, 0.05 mol) in water (150mL). Solid K₂CO₃ was added to bring the pH to 9 and the mixture wasextracted 2× CH₂Cl₂, washed 1× brine, and dried over Na₂SO₄. Evaporationyielded an oil, which was filtered through silica gel, eluting withCH₂Cl₂-EtOAc which yielded 3.8 g oil (89%), which was used withoutfurther purification. MS (APCI) m/z 240 (M), 239 (M−1); IR (Film) 2215cm⁻¹.

[0148] BOC-IsobutylGABA amidoxime (E)

[0149] A solution of hydroxylamine was prepared by adding triethylamine(7.62 g, 0.075 mol) to a suspension of hydroxylamine hydrochloride (5.21g, 0.075 mol) in DMSO (25 mL). After 15 minutes, the triethylaminehydrochloride was filtered off, and BOC-IsobutylGABA nitrile (3.61 g,0.015 mol) was added to the filtrate. The mixture was heated at 75° C.for 17 hours. The mixture was diluted with water and extracted 3× EtOAc.The extracts were washed 2× brine, dried over Na₂SO₄, and evaporated togive an oil which was filtered through a short silica gel column,eluting with CH₂Cl₂-EtOAc to give 3.2 g (78%) oil. ¹H NMR (CDCl₃) δ0.84(d, 6H, J=6.35 Hz), 1.11 (m, 2H), 1.40 (s, 9H), 1.63 (m, 1H), 3.05 (m,1H), 3.15 (m, 1H), 4.85 (m, 1H), 5.43 (m 1H); MS (APCI) 274 (M+1).

[0150] BOC-IsobutylGABA oxadiazolonethione (F)

[0151] A solution containing BOC-Isobutyl GABA amidoxime (0.5 g, 0.00183mol), DBU (1.12 g, 0.00736 mol) and 90% 1,1′-thiocarbonyldiimidazole(0.398 g, 0.002 mol) in MeCN (12 mL) was stirred at room temperature 16hours. The reaction mixture was evaporated to dryness, taken up inEtOAc, and washed with KHSO₄ solution. The EtOAc layer was extractedwith 1N NaOH (100 mL). The alkaline extract was washed with Et₂O andacidified with saturated KH₂PO₄ and extracted 3× EtOAc. The extractswere washed 1× water, 1× brine and dried over MgSO₄. Evaporation yieldedan oil, 0.25 g (43%). ¹H NMR (CDCl₃) δ0.84 (d, 6H, J=6.59 Hz), 1.1 (m,2H), 1.41 (s, 9H), 1.65 (m, 1H), 1.85 (m, 1H), 2.60 (m, 2H), 3.1 (m,2H), 4.94 (m, 1H), 12.8 (s, 1H). MS (APCI) 316 (M+1).

[0152] IsobutylGABA Oxadiazolonethione (G) Is Also Named3-(2-Aminomethyl-4-methyl-pentyl)-4H-[1,2,4]oxadiazole-5-thione; HCl

[0153] BOC-IsobutylGABA oxadiazolonethione (0.25 g, 0.79 mmol) was takenup in 4 M HCl in dioxane (10 mL) at room temperature for 1 hour.Evaporation followed by recrystallization of the residue from MeCNyielded cream-colored crystals, 0.108 g, mp 183-185° C. ¹H NMR (DMSO-d₆)δ0.84 (d, 6H, J=6.59 Hz), 1.1 (m, 2H), 1.41 (s, 9H), 1.65 (m, 1H), 0.80(d, 6H, J=6.59 Hz), 1.06 (m, 1H), 1.25 (m, 1H), 1.55 (m, 1H), 2.1 (m,1H), 2.7 (m, 4H), 7.95 (s, 3H); MS (APCI) 216 (M+1). Anal. Calcd forC₉H₁₇N₃OS.HCl: C, 42.93; H, 7.21; N, 16.69; Cl, 14.08. Found: C, 43.38;H, 7.24; N, 16.29; Cl, 14.17.

EXAMPLE 3

[0154] IsobutylGABA Oxadiazolone (J) Is Also Named3-(2-Aminomethyl-4-methyl-pentyl)-4H-[1,2,4]oxadiazole-5-one; HCl

[0155] BOC-IsobutylGABA amidoxime carbamate (H)

[0156] Isobutyl chloroformate (0.253 g, 0.00185 mol) was added dropwiseto a solution of BOC-IsobutylGABA amidoxime (0.5 g, 0.00183 mol) andpyridine (0.158 g, 0.002 mol) in DMF (10 ml) at 0° C. After 30 minutesat that temperature, the reaction mixture was diluted with water andextracted 3× EtOAc. The extracts were washed 1× water, 1× brine anddried over MgSO₄. Evaporation yielded an oil, 0.7 g (100%) which wasused without further purification. MS (APCI) m/z 374 (M+1).

[0157] BOC-IsobutylGABA oxadiazolone (I)

[0158] BOC-IsobutylGABA amidoxime carbamate (0.7 g, 0.00183 mol) wastaken up in xylene (20 mL) and heated under reflux 2 hours. Evaporationyielded a dark glassy oil which was taken up in Et₂O and extracted with1N NaOH. The alkaline phase was acidified with saturated KH₂PO₄ andextracted 3× EtOAc. The extracts were washed with brine, dried overMgSO4 and evaporated to yield a brown oil, 0.25 g (46%), which was usedwithout further purification. MS (APCI) m/z 300 (M+1).

[0159] IsobutylGABA oxadiazolone (J) Is Also Named3-(2-Aminomethyl-4-methyl-pentyl)-4H-[1,2,4]oxadiazole-5-one; HCl

[0160] BOC-IsobutylGABA oxadiazolone(0.25 g, 0.835 mmol) was taken up in4 M HCl in dioxane and allowed to stand 2.5 hours Evaporation followedby recrystallization of the residue from MeCN-Et₂O yielded a tan solid,53 mg (27%), mp 181-184° C. ¹H NMR (DMSO-d₆) δ0.80 (d, 6H, J=6.35 Hz),1.1 (m, 2H), 1.25 (s, 9H), 1.60 (m, 1H), 2.10 (m, 1H), 2.5-2.8 (m, 4H),7.95 (s, 3H), 12.39 (s, 1H). MS (APCI) 216 (M+1). Anal. Calcd forC₉H₁₇N₃O₂.HCl: C, 45.86; H, 7.70; N, 17.83; Cl, 15.04. Found: C, 45.40;H, 7.55; N, 16.79; Cl, 15.81.

EXAMPLE 4 Preparation of (2-Aminomethyl-4-methyl-pentyl)-phosphonic acid(9)

[0161]

[0162] 1. Preparation of 2-Isobutyl-succinic acid-4-t-butyleser-1-methyl ester (2): 4-methylpentanoic acid methyl ester (10.0 g,76.8 mmol) is added to a solution of LDA in 150 mL of THF at −78° C.under Ar. After 15 minutes, the anion solution is added by cannula to asolution of t-butyl bromoacetate (22.5 g, 115.2 mmol) in 50 mL of THF at−78° C., and the solution is stirred for 45 minutes. The reactionmixture is then warmed to room temperature, and treated with 100 mL ofsaturated KH₂PO₄. The THF is evaporated, and the organics are extractedinto Et₂O (3×50 mL). The Et₂O is washed with 10% Na₂S₂O₃ and dried withMgSO₄. The solvent is evaporated, and the remaining oil is distilledunder vacuum (0.1 mm Hg) to give 11.1 g (59% yield) of2-isobutyl-succinic acid-4-t-butyl ester-1-methyl ester boiling at 65°C. to 72° C. NMR (H¹, 400 MHz, CDCl₃) δ0.9 (6H, m); δ1.2 (1H, m); δ1.4(9H, s); δ1.5 (2H, m); δ2.3 (1H, dd); δ2.5 (1H, dd); δ2.8 (1H, m); δ3.6(3H, s).

[0163] 2. Preparation of 2-Isobutyl-succinic acid-4-t-butyl ester (3):2-isobutyl-succinic acid-4-t-butyl ester-1-methyl ester (11.1 g, 45.4mmol) and LiOH.H₂O (2.0 g, 47.7 mmol) are stirred in 180 mL of 3:1IPA/H₂O at room temperature overnight. The reaction mixture is extractedwith Et₂O (3×25 mL). The aqueous phase is acidified to pH=4, withsaturated KH₂PO₄ and extracted with Et₂O (3×50 mL). The Et₂O is driedover MgSO₄, and evaporated to give 8.0 g (77% yield) of2-isobutyl-succinic acid-4-t-butyl ester as an oil. NMR (H¹, 400 MHz,CDCl₃) δ0.9 (6H, m); δ1.3 (1H, m); δ1.4 (9H, s); δ1.6 (2H, m); δ2.3 (1H,dd); δ2.6 (1H, dd); δ2.8 (1H, m).

[0164] 3. Preparation of 4-Isobutyl-dihydro-furan-2-one (4): A solutionof 2-isobutyl-succinic acid-4-t-butyl ester (8.0 g, 34.7 mmol) in 100 mLof THF is cooled to 0° C. under Ar and borane dimethyl sulphide complex(2.6 g, 34.7 mmol) is added. The reaction mixture is stirred at 0° C.for 10 minutes, and at room temperature overnight. The solution iscooled to 0° C. and 100 mL of MeOH is added. The solvents areevaporated, and the remaining oil is dried under hi-vacuum for 2 hrs.The oil remaining is taken up in 100 mL of THF, and a catalytic amountof p-toluene sulfonic acid is added. The solution is warmed to refluxovernight. After being cooled to room temperature, the solvent isevaporated, and the oil is taken up in Et₂O (100 mL). The Et₂O solutionis extracted with 2.0N Na₂CO₃ (2×50 mL) followed by 100 mL of brine anddried over MgSO₄. Evaporation of Et₂O followed by medium pressurechromatography (MPLC) of the remaining oil in 20% EtOAc/Hexanes gives4.4 g (89% yield) of 4-isopropyl-dihydro-furan-2-one as an oil. NMR (H¹,400 MHz, CDCl₃) δ0.9 (6H, m); δ1.3 (2H, dd); δ1.5 (1H, m); δ2.1 (1H, m);δ2.6 (2H, m); δ3.6 (1H, m); δ4.4 (1H, m).

[0165] 4. Preparation of 3-Bromomethyl-3-isobutyl-propionic acid ethylester (5): A solution of 4-isopropyl-dihydro-furan-2-one (4.4 g, 30.9mmol) in absolute EtOH (50 mL) is cooled to 0° C. and saturated with HBrby passing HBr gas through it for 10 minutes. The solution is warmed toroom temperature and stirred for 2.5 hours. It is diluted with 150 mL ofbrine and extracted with Et₂O (3×100 mL). Drying over MgSO₄ followed byevaporation of the solvent gives 4.9 g (63% yield) of3-bromomethyl-3-isobutyl-propionic acid ethyl ester as an oil. NMR (H¹,300 MHz, CDCl₃) δ0.9 (6H, d); δ1.3 (5H, m); δ1.6 (1H, m); δ2.3 (1H, m);δ2.5 (1H, dd); δ3.2 (1H, dd); δ3.6 (1H, dd); δ4.1 (2H, q).

[0166] 5. Preparation of 3-(Diethoxy-phosphorylmethyl)-5-methyl-hexanoicacid ethyl ester (6): 3-bromomethyl-3-isobutyl-propionic acid ethylester (4.6 g, 18.3 mmol) is warmed in a 170° C. oil bath under Ar.Triethyl phosphite (3.6 g, 22 mmol) is added dropwise over 2 hours. Whenaddition is complete, the oil bath temperature is raised to 190° C. for4 hours. The reaction mixture is cooled to room temperature, and theproduct is purified by MPLC in EtOAc to give 2.7 g (48% yield) of3-(Diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid ethyl ester. NMR(H¹, 400 MHz, CDCl₃) δ0.8 (6H, d); δ1.2 (5H, m); δ1.3 (6H, m); δ1.6 (1H,m); δ1.7 (1H, d); δ1.8 (1H, d); 2.3 (2H, m); δ2.5 (1H, dd); δ4.1 (6H,m).

[0167] 6. Preparation of 3-(Diethoxy-phosphorylmethyl)-5-methyl-hexanoicacid (7): 3-(Diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid ethylester (1.0 g, 3.2 mmol) and NaOH (1.8 mL, 2.0 M) are combined in 10 mLof EtOH at 0° C. After 15 minutes, the reaction mixture is warmed toroom temperature and stirred overnight. The EtOH is evaporated, and 50mL of 2.0 M NaOH is added. The solution is extracted with Et₂O (2×50mL), and then acidified to pH=1 with concentrated HCl. The acidicsolution is extracted with EtOAc (3×50 mL), and the combined extractsare dried over MgSO4 and evaporated to give 0.65 g (72% yield) of3-(Diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid as an oil. NMR (H¹,400 MHz, CDCl₃) δ0.9 (6H, d); δ1.3 (8H, m); δ1.6 (1H, m); δ1.8 (2H, m);δ2.3 (1H, m); δ2.5 (2H, m); δ4.1 (4H, m).

[0168] 7. Preparation of[2-(Benzyloxycarbonylamino-methyl)-4-methyl-pentyl]-phosphonic aciddiethyl ester (8): A solution3-(Diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid (0.65 g, 2.3 mmol),diphenyl-di-phosphoryl-azide (0.76 g, 2.8 mmol), triethyl amine (0.47 g,4.6 mmol), and benzyl alcohol (0.5 g, 4.6 mmol) in 100 mL of toluene iswarmed to reflux overnight. The toluene is evaporated, and the remainingoil is taken up in 50 mL of EtOAc. The EtOAc solution is washed with1.0N HCl (2×50 mL), saturated NaHCO₃ (2×50 mL), and 50 mL of brine.Drying over Na₂SO₄ followed by evaporation of the solvent gives an oilwhich is purified by MPLC in EtOAc. Yield of[2-(Benzyloxycarbonylamino-methyl)-4-methyl-pentyl]-phosphonic aciddiethyl ester=0.46 g (52%). NMR (H¹, 400 MHz, CDCl₃) δ0.9 (6H, m);δ1.1-1.4 (9H, m); 1.7 (2H, m); δ2.0 (1H, m); δ3.1 (1H, m); δ3.3 (1H, m);δ4.1 (4H, q); δ5.0 (2H, s); δ5.7 (1H, bs); δ7.3 (5H, m).

[0169] 8. Preparation of (2-Aminomethyl-4-methyl-pentyl)-phosphonic acid(9): A solution of[2-(Benzyloxycarbonylamino-methyl)-4-methyl-pentyl]-phosphonic aciddiethyl ester (0.46 g, 1.2 mmol) in 20 mL of 47% aqueous HBr is warmedat reflux overnight. The solution is cooled to room temperature, and theH₂O is evaporated. The remaining solid is taken up in 10 mL of H₂O,filtered through Celite® 545, and passed through a Dowex® 50 ionexchange column (Bed Volume=30 mL). The column is eluted with 200 mL ofH₂O, 150 mL of 3% NH₄OH, and 150 mL of 10% NH₄OH. The basic eluates arecombined and evaporated to give 0.14 g of a white solid. After dryingunder vacuum at 60° C. with P₂O₂, the yield of(2-Aminomethyl-4-methyl-pentyl)-phosphonic acid=0.11 g (47%). NMR (H¹,400 MHz, CD₃OD) δ0.9 (6H, m); δ1.2 (2H, t); δ1.4 (1H, m); δ1.7 (2H, m);δ2.1 (1H, m); δ2.7 (1H, dd); δ3.0 (1H, dd). MS (m/e) 196 (M+1, 100%).Analysis for C₇H₁₈NO₃P: Calculated: C, 43.07; H, 9.29; N, 7.18. Found:C, 43.08; H, 8.62; N, 6.89.

What is claimed is:
 1. A compound of the formula

or a pharmaceutically acceptable salt thereof wherein: n is an integerof from 0 to 2; R is sulfonamide, amide, phosphonic acid, heterocycle,sulfonic acid, or hydroxamic acid; A is hydrogen or methyl; and B is

straight or branched alkyl of from 1 to 11 carbons, or—(CH₂)₁₋₄—Y—(CH₂)₀₋₄-phenyl wherein Y is —O—, —S—, —NR′₃ wherein R′₃ isalkyl of from 1 to 6 carbons, cycloalkyl of from 3 to 8 carbons, benzylor phenyl wherein benzyl or phenyl can be unsubstituted or substitutedwith from 1 to 3 substituents each independently selected from alkyl,alkoxy, halogen, hydroxy, carboxy, carboalkoxy, trifluoromethyl, andnitro, provided that when A is hydrogen, B is not isobutyl.
 2. Acompound of the formula

or a pharmaceutically acceptable salt thereof wherein: n is an integerof from 0 to 2; and R is sulfonamide, amide, phosphonic acid,heterocycle, sulfonic acid, or hydroxamic acid, provided that when R isheterocycle, the heterocycle is not


3. A compound according to claim 1 wherein n is 1 and R is


4. A compound according to claim 1 wherein R is a sulfonamide selectedfrom —NHSO₂R¹⁵ or —SO₂NHR¹⁵ wherein R¹⁵ is straight or branched alkyl ortrifluoromethyl.
 5. A compound according to claim 2 wherein R is asulfonamide selected from —NHSO₂R¹⁵ or —SO₂NHR¹⁵ wherein R¹⁵ is straightor branched alkyl or trifluoromethyl.
 6. A compound according to claim 1named: 3-(3-Amino-2-cyclopentyl-propyl)-4H-[1,2,4]oxadiazol-5-one;3-(3-Amino-2-cyclopentyl-propyl)-4H-[1,2,4]thiadiazol-5-one;2-Cyclopentyl-3-(2-oxo-2,3-dihydro-2λ⁴-[1,2,3,5]oxathiadiazol-4-yl)-propylamine;3-(3-Amino-2-cyclobutyl-propyl)-4H-[1,2,4]oxadiazol-5-one;3-(3-Amino-2-cyclobutyl-propyl)-4H-[1,2,4]thiadiazol-5-one; and2-Cyclobutyl-3-(2-oxo-2,3-dihydro-2λ⁴-[1,2,3,5]oxathiadiazol-4-yl)-propylamine.7. A compound according to claim 2 named:(2-Aminomethyl-4-methyl-pentyl)-phosphonic acid.
 8. A compound accordingto claim 1 wherein R is a phosphonic acid, —PO₃H₂.
 9. A compoundaccording to claim 2 wherein R is a phosphonic acid, —PO₃H₂.
 10. Acompound according to claim 1 wherein R is a heterocycle selected from


11. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 12. A pharmaceutical composition comprising atherapeutically effective amount of a compound according to claim 2 anda pharmaceutically acceptable carrier.
 13. A method for treatingepilepsy, faintness attacks, hypokinesia, cranial disorders,neurodegenerative disorders, depression, anxiety, panic, pain,neuropathological disorders, gastrointestinal damage, inflammation orgastrointestinal disorders comprising administering a therapeuticallyeffective amount of a compound according to claim 1 to a mammal in needof said treatment.
 14. A method for treating epilepsy, faintnessattacks, hypokinesia, cranial disorders, neurodegenerative disorders,depression, anxiety, panic, pain, neuropathological disorders,gastrointestinal damage, inflammation or gastrointestinal disorderscomprising administering a therapeutically effective amount of acompound according to claim 2 to a mammal in need of said treatment. 15.A method according to claim 13 wherein the gastrointestinal disorder isirritable bowel syndrome.
 16. A method according to claim 14 wherein thegastrointestinal disorder is irritable bowel syndrome.